Angiopoietin-2: A Potential Mediator of the Glycocalyx Injury in Adult Nephrotic Patients

Abstract

Introduction: Glomerulopathy is a group of diseases that affect mainly young adults between the ages of 20 and 40 years. Recently, it has been demonstrated that syndecan-1, a biomarker of endothelial glycocalyx damage, is increased in nephrotic patients with near-normal renal function and it is important to endothelial dysfunction in these patients. Angiopoietin-2 (AGPT2) is an endothelial growth factor that promotes cell derangement. Here we evaluated AGPT2 levels in patients with nephrotic syndrome, near-normal renal function and the possible interaction of AGPT2 with endothelial glycocalyx derangement. Methods: This was a cross-sectional study performed from January through November 2017. Adult patients (age > 18 years) with nephrotic syndrome and without immunosuppression were included. Blood samples were drawn after a 12 h fast for later measurement of syndecan-1 and AGPT2. Mediation analyses were performed to assess the hypothesized associations of nephrotic syndrome features and AGPT2 with syndecan-1. Results: We included 65 patients, 37 (56.9%) of them female, with primary glomerular disease. Syndecan-1 in nephrotic patients was higher than in control individuals (102.8 ± 36.2 vs. 28.2 ± 9.8 ng/mL, p < 0.001). Correlation of syndecan-1 with the main features of nephrotic syndrome after adjustment for age and estmmated glomerular filtration rate (eGFR) demonstrated that syndecan-1 was significantly associated with 24-h urinary protein excretion, total cholesterol, LDL (low density lipoprotein)-cholesterol, HDL (high-density lipoprotein)-cholesterol, and triglycerides. Angiopoietin-2 was independently associated with serum albumin, 24 h urinary protein excretion, total cholesterol, and LDL-cholesterol, in addition to being strongly associated with syndecan-1 (0.461, p < 0.001). The results of the mediation analyses showed that the direct association between LDL-cholesterol and syndecan-1 was no longer significant after AGPT-2 was included in the mediation analysis. AGPT2 explained 56% of the total observed association between LDL-cholesterol and syndecan-1. Conclusion: The association between LDL-cholesterol and glycocalyx derangement in nephrotic patients is possibly mediated by AGPT2.

Assessing coagulopathy and endothelial dysfunction in pediatric venous malformation: A thromboelastometry and syndecan‐1 study

“…Endothelial dysfunction, resulting from modifications in the composition of the glycocalyx, is a key factor in certain pathologies with a high incidence and may act as a prothrombotic factor 43–47 . In our study, we identified a significant decrease in SDC‐1 within the endothelial lumen compared to extralesional samples.…”

Vascular Permeability: Regulation Pathways and Role in Kidney Diseases

“…Similar to research studies on VEGF, these data are obtained mainly from mouse models [19-21, 23, 27], human EC lines [19, 21, 23, 27], and mouse EC lines [21, 24-26], demonstrating the effects of the Angpt/Tie signal via the transcellular [21] and paracellular [19, 20, 24, 25] pathways. The clinical trial [22] provides evidence of how Angpt2 modulates VP via glycocalyx damage in patients, and more clinical studies are required to add to the reliability of current conclusions.…”

“…Also, Angpt2 decreases claudin-5 expression in TJs, increases caveolin-1 expression to support the transcellular pathway, and stimulates pericyte detachment and migration to mediate VP [21]. Another possible mechanism of Angpt2-induced VP may involve the damage of the endothelial surface glycocalyx that is important to endothelial dysfunction, as a clinical trial suggests that increased Angpt2 may mediate the association between low-density lipoprotein-cholesterol and glycocalyx injury marked by the biomarker syndecan-1 in patients with DOI: 10.1159/000514314 nephrotic syndrome [22]. Tie1 is less characterized than Tie2, which might directly interact with Tie2 to regulate the Angpt/Tie2 pathway, and its deletion tightens the AJs by upregulating VE-cadherin expression [23].…”

Case Report: Novel Dietary Supplementation Associated With Kidney Recovery and Reduction in Proteinuria in a Dialysis Dependent Patient Secondary to Steroid Resistant Minimal Change Disease

“…Angiopoietin-2 (ANGPT2) is an endothelial growth factor that promotes cell derangement ( 12 ). Indeed, the linkage between endothelial glycocalyx damage, proteinuria and systemic vascular dysfunction is becoming clearer ( 13 ). Therefore, loss of the endothelial surface layer appears to be a link between albuminuric kidney disease and systemic vascular dysfunction, providing a potential therapeutic target for proteinuric kidney disease.…”